ENZYME REACTORS FOR THE SYNTHESIS OF PEPTIDE INHIBITORS

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Demand is high for synthetic peptides that inhibit aspartyl proteases because of the promise they show for the treatment of serious health disorders such as hypertension. However, conventional techniques for the large-scale preparation of synthetic peptides have drawbacks (e.g., racemization of components, hazards associated with reagents, and laborious purification steps). This program is aimed at the development of a novel peptide-synthesis process that overcome these drawbacks. The approach is based on the use of an enzyme-coated carrier that is used to couple dipeptide derivative and statine analogs to form peptide inhibitors. In Phase I, we successfully demonstrated feasibility, using the enzyme-coated-carrier process to synthesize three model renin inhibitors. In Phase II, we propose to characterize the enzyme-coated-carrier process and develop the information necessary to commercialize the process in Phase III. Specifically, we plan to characterize the process for the production of renin inhibitors, investigate the effect of process variables, demonstrate widespread applicability of the process, identify scale-up tissues, and demonstrate the technical and economic feasibility of the process. We expect to commercialize this process in Phase III through collaboration with a major U.S. pharmaceutical company.